Method for preparation of a high concentration liquid formulation of an antibody

Abstract

The present invention provides a method for preparation of a high concentration liquid formulation (HCLF) of an antibody or a fragment thereof. The present invention also relates to a method for stabilizing an anti-CD20 antibody or a fragment thereof in a liquid pharmaceutical formulation. Furthermore, the present invention relates to a liquid pharmaceutical formulation of a veltuzumab antibody or a fragment thereof comprising at least 155 mg/mL of a veltuzumab antibody or a fragment thereof.

1 . A method for preparation of a high concentration liquid formulation of an antibody having a concentration C H  of the antibody, comprising the steps of:
 a) providing a solution containing the antibody in a starting concentration C S ;   b) ultrafiltering the solution of step (a) in order to obtain a solution having an intermediate concentration C I  of the antibody, wherein C I  is at least about 260 mg/mL; and   c) diluting the solution of step (b) to a concentration C H  of the antibody in order to obtain the high concentration liquid formulation.   
     
     
         2 . The method according to  claim 1 , wherein the solution of step (a) further contains a buffering agent. 
     
     
         3 . The method according to  claim 1 , further comprising between step (a) and step (b) a step of diafiltering the solution of step (a) with a buffer solution. 
     
     
         4 . The method according to  claim 1 , wherein the solution which is subjected to ultrafiltering in step (b) contains 40 mM histidine and has a pH value of 5.45. 
     
     
         5 . The method according to  claim 1 , wherein the solution which is subjected to ultrafiltering in step (b) is essentially free of or does not contain a tonicity modifying agent. 
     
     
         6 . The method according to  claim 1 , wherein the solution which is subjected to ultrafiltering in step (b) is essentially free of or does not contain a surfactant. 
     
     
         7 . The method according to  claim 1 , wherein the antibody is an anti-CD20 antibody and/or an IgG antibody. 
     
     
         8 . The method according to  claim 1 , wherein the high concentration liquid formulation has an antibody concentration C H  of at least 155 mg/mL. 
     
     
         9 . The method according to  claim 1 , wherein step (b) is performed in an ultrafiltration device and further comprising between step (b) and step (c) a step of flushing the ultrafiltration device with a buffer solution. 
     
     
         10 . A method for stabilizing an anti-CD20 antibody or a fragment thereof in a liquid pharmaceutical formulation in a concentration of at least 155 mg/mL by combining the antibody or fragment thereof which has not been freeze-dried with an aqueous solution comprising an amino acid. 
     
     
         11 . The method according to  claim 7 , wherein the anti-CD20 antibody is a veltuzumab antibody. 
     
     
         12 . Liquid pharmaceutical formulation of a veltuzumab antibody or a fragment thereof comprising at least 155 mg/mL veltuzumab antibody or a fragment thereof and an amino acid. 
     
     
         13 . The liquid pharmaceutical formulation according to  claim 12 , wherein the concentration of the veltuzumab antibody or a fragment thereof is at least 175 mg/mL. 
     
     
         14 . The liquid pharmaceutical formulation to  claim 12 , wherein the concentration of the veltuzumab antibody or a fragment thereof is at least 200 mg/mL. 
     
     
         15 . The liquid pharmaceutical formulation according to  claim 12 , wherein the concentration of the amino acid is in the range of 1 mM to 100 mM. 
     
     
         16 . The liquid pharmaceutical formulation according to  claim 15 , wherein the concentration of the amino acid is in the range of 10 mM to 60 mM. 
     
     
         17 . The liquid pharmaceutical formulation according to  claim 12 , further comprising a surfactant. 
     
     
         18 . The liquid pharmaceutical formulation according to  claim 17 , wherein the surfactant is a polysorbate. 
     
     
         19 . The liquid pharmaceutical formulation according to  claim 17 , wherein the surfactant is present in a concentration of at least 0.01 mg/mL. 
     
     
         20 . The liquid pharmaceutical formulation according to  claim 12 , further comprising a tonicity modifying agent. 
     
     
         21 . The liquid pharmaceutical formulation according to  claim 20 , wherein the tonicity modifying agent is sorbitol and/or mannitol. 
     
     
         22 . The liquid pharmaceutical formulation according to  claim 12 , having a pH value in the range of 4.8 to 7.0. 
     
     
         23 . The liquid pharmaceutical formulation according to  claim 12  comprising
 a) at least 160 mg/mL veltuzumab antibody or a fragment thereof; 
 b) 220 mM sorbitol; 
 c) 30 mM histidine; 
 d) 0.2 mg/mL polysorbate 20; and 
 
       having a pH value in the range of 5.0 to 6.0. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A method of treating cancer or a non-malignant disease in a patient comprising administering to a patient in need thereof the liquid pharmaceutical formulation according to  claim 12 . 
     
     
         27 . A method of treating a disease selected from the group consisting of Burkitt Lymphoma, Epstein-Barr Virus Infections, B-Cell Leukemia, Chronic Lymphocytic B-Cell Leukemia, Acute Lymphoblastic Leukemia, Lymphoid Leukemia, Prolymphocytic Leukemia, Hairy Cell Leukemia, Multiple Myeloma, B-Cell Lymphoma, Marginal Zone B-Cell Lymphoma, Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, Immunoblastic Large-Cell Lymphoma, Mantle-Cell Lymphoma, Non-Hodgkin Lymphoma, Lymphomatoid Granulomatosis, Plasma Cell Neoplasms, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Tumor Virus Infections, Waldenstrom Macroglobulinemia, Rheumatoid Arthritis, Immunoproliferative Disorders, Prolymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Immunoblastic Large-Cell Lymphoma, Mantle-Cell Lymphoma, Lymphomatoid Granulomatosis, Lymphoproliferative Disorders, Paraproteinemias, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Thrombocytopenic Purpura, Idiopathic Thrombocytopenic Purpura (ITP), Blood Coagulation Disorders, Blood Platelet Disorders, Blood Protein Disorders, Hematologic Diseases, Hemorrhagic Disorders, Hemostatic Disorders, Lymphatic Diseases, Purpura, Thrombocytopenia, Thrombotic Microangiopathies, Haemostatic Disorders, Vascular Diseases, Systemic lupus erythematosus (SLE), Multiple sclerosis, Rheumatic Diseases, Juvenile rheumatoid arthritis, Osteoarthritis, Psoriatic arthritis, Psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Connective Tissue Diseases, Herpesviridae Infections, and DNA Virus Infections in a patient comprising administering to a patient in need thereof the liquid pharmaceutical formulation according to  claim 12 .